Methods of treating hyperalgesia

ABSTRACT

This application describes compounds and methods that can be used to treat, reverse, or avoid hyperalgesia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/267,144, filed Dec. 14, 2015, which is incorporated by reference inits entirety. The present application is also related to U.S.Non-Provisional application Ser. No. 13/428,849, filed Mar. 23, 2012,Provisional Application No. 61/596,808 filed Feb. 9, 2012, and U.S.Provisional Application No. 61/466,809 filed Mar. 23, 2011, each ofwhich is incorporated herein by reference in its entirety.

FIELD

This application relates to a family of compounds acting as opioidreceptor ligands and methods of using such compounds for treating orreversing hyperalgesia, induced hyperalgesia, decreasing nociceptivesensitization, and the like.

BACKGROUND

Opioid receptors (ORs) mediate the actions of morphine and morphine-likeopioids, including most clinical analgesics. Three molecularly andpharmacologically distinct opioid receptor types have been described: δ,κ and μ. Furthermore, each type is believed to have sub-types. All threeof these opioid receptor types appear to share the same functionalmechanisms at a cellular level. For example, activation of the opioidreceptors causes inhibition of adenylate cyclase, and recruitsβ-arrestin.

When therapeutic doses of morphine are given to patients with pain, thepatients report that the pain is less intense, less discomforting, orentirely gone. In addition to experiencing relief of distress, somepatients experience euphoria. However, when morphine in a selectedpain-relieving dose is given to a pain-free individual, the experienceis not always pleasant; nausea is common, and vomiting may also occur.Drowsiness, inability to concentrate, difficulty in mentation, apathy,lessened physical activity, reduced visual acuity, and lethargy mayensue. Additionally, those administered morphine and similar non-biasedligands can suffer from hyperalgesia. If the cause is due to an opioidtherapeutic, it can be referred to as Opioid Induced Hyperalgesia (OIH).

There is a continuing need for new OR modulators to be used astherapeutics that do not cause hyperalgesia or that can be used to treatpeople that suffer from hyperalgesia, induced by opioids or otherwise.The present embodiments satisfy these needs as well as other.

SUMMARY

This application describes opioid receptor (OR) ligands. It alsodescribes methods of treating or reversing hyperalgesia, such as but notlimited to, opioid induced hyperalgesia. Accordingly, in someembodiments, methods of treating hyperalgesia in a subject are provided.In some embodiments, methods of reversing hyperalgesia, including butnot limited to, opioid induced hyperalgesia, in a subject are provided.In some embodiments, the methods comprise administering to the subject acompound of any formula described herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, methods of decreasing nociceptive sensitization ina subject are provided. In some embodiments, the methods compriseadministering to the subject a compound of any formula described herein,or a pharmaceutically acceptable salt thereof.

In some embodiments, methods of treating pain in a subject are provided.In some embodiments, the methods comprise administering an opioidagonist to the subject until the first opioid increases nociceptivesensitization in the subject; and administering to the subject withincreased nociceptive sensitization a compound of any formula describedherein, or a pharmaceutically acceptable salt thereof.

In some embodiments, methods of treating pain in an opioid exposedsubject are provided. In some embodiments, the methods compriseadministering an opioid agonist to the subject; and administering to thesubject of step a compound of any formula described herein, or apharmaceutically acceptable salt thereof in the absence of the opioid.

In some embodiments, the compound of any formula or described herein, ora pharmaceutically acceptable salt thereof has a formula of Formula I:

In the structure above, variables A₁, A₂, A₃, A₄, A₅, B₁, B₂, B₃, B₄,B₅, and D₁ can be selected from the respective groups of chemicalmoieties later described. OR ligand derivatives and mimetics are alsoprovided.

In some embodiments, the compound has a formula of

or a pharmaceutically acceptable salt thereof, wherein D₁ is anoptionally substituted aryl; and B₅ is an optionally substitutedpyridyl.

This application also describes pharmaceutical compositions comprisingone or more compounds as described in this application apharmaceutically acceptable carrier. Naturally, the compounds describedherein can be employed in any form, such as a solid or solution (e.g.,aqueous solution) as is described further below. The compounds describedherein, for example, can be obtained and employed in a lyophilized formalone or with suitable additives.

In some embodiments, uses of the compounds, or pharmaceuticallyacceptable salts thereof, in the preparation of a medicament for thetreatment or reversal of hyperalgesia, opioid induced hyperalgesia, andthe like are provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates that biased ligands described herein do not inducehyperalgesia.

FIG. 2 illustrates that biased ligands can reverse opioid inducehyperalgesia.

DETAILED DESCRIPTION

This application describes a family of compounds, OR ligands, with aunique profile.

The compounds described herein act as agonists or antagonists of opioidreceptor (OR)-mediated signal transduction. The ligands of thesereceptors can be used to treat pathologies associated with ORs includingpain and pain related disorders, such as, but not limited to, opioidinduced hyperalgesia and nociceptive sensitization.

In some embodiments, compounds also comprise Formula I:

wherein: A₁ is null, CH₂, CHR₁, CR₁R₂, CH, CR₁, O, S, SO, SO₂, NH orNR₁; A₂ is null, CH₂, CHR₅, CR₅R₆, CH, CR₅, O, S, SO, SO₂, NH or NR₅; A₃is null, CH₂, CHR₇, CR₇R₈, O, S, SO, SO₂, NH, NR₇, CH or CR₇; A₄ isnull, CH₂, cycle of the formula C(CH₂)_(n), where n=2-5, CHR₉, CR₉R₁₀,O, S, SO, SO₂, NH, NR₉, CH or CR₉; and A₅ is null, CH₂, CHR₁₁, CR₁₁R₁₂,CH₂CH₂, CHR₁₁CH₂, CH₂CHR₁₁, CHR₁₁CHR₁₂, O, S, SO, SO₂, NH, NR₁₁, CH orCR₁₁.

No more than 2 out of 5 A_(a) (specifically A₁, A₂, A₃, A₄, A₅) can benull at the same time. The number of heteroatoms from A₁ to A₅ cannotexceed 2 at the same time, and O—O, S—O; S—S; S—N fragments in the ringstructure are excluded from this composition.

The ring containing A₁, A₂, A₃, A₄, A₅ and the carbon connected to D₁can be fused with another ring, such as benzene, pyridine, pyrimidine,furan, thiophene or pyridazine, but not limited to these examples, wherethe resulting bicycle is chemically stable and synthetically accessible.It is also understood that the above-mentioned fused rings could bemultiply substituted with cyano, halogen, alkyl, branched alkyl,halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino,alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, and other smallsubstitution groups. The bonds between A₁ and A₂, A₂ and A₃, A₃ and A₄,A₄ and A₅ can independently be a single bond or a double bond. The bondsbetween A₁ and A₂, A₂ and A₃, A₃ and A₄, A₄ and A₅ cannot be a doublebond at the same time.

A₂ and A₄ can be connected by a carbon bridge. Examples of such a bridgeinclude —CH₂—, and —CH₂CH₂—.

B₁ is CH₂, CHR₁₃, CR₁₃R₁₄, O, S, SO, SO₂, NH, NR₁₃, CR₁₃ or CO. B₂ isCH₂, CHR₁₅, CR₁₅R₁₆, CR₁₅ or CO. B₃ is H, alkyl, branched alkyl,halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branchedalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or alkyl sulfonyl. B₄ isnull, C₁-C₆ alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀ or CO. In someembodiments, when B₄ is an alkyl one or more of the hydrogens can bereplaced with a deuterium. B₅ is alkyl, branched alkyl, halogenatedalkyl, carbocycle-substituted alkyl, aryl, carbocycle or arylalkyl.

Aryl, carbocycle (non-aromatic)/heterocycle (non-aromatic with 1-3heteroatoms, including O, N, S) are either unsubstituted, or substitutedwith small substitution groups. Small substitution groups can be cyano,halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy,amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aryl, arylalkyl, carbocycle or carbocycle-alkyl. In some embodiments,the small substitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃,CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt,O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesuflonyl, Ph,benzyl, MeSO₂, formyl, and acetyl.

Carbocycle may contain double bonds, but they should not be aromatic.

D₁ is an aryl group or a carbocycle.

An aryl group is either a monocyclic aromatic group or a bicyclicaromatic group, which may contain heteroatoms in the aromatic group(e.g. heteroaryl). The following structures are some examples ofrepresentative aryl groups, but the aryl groups are not limited to thoseexamples:

Carbocycle is either a monocyclic or a bicyclic non-aromatic ringsystem. The following structures are some examples of representativecarbocycle, but the carbocycle is not limited to those examples:

wherein X₁, and X₂ in the carbocycle examples are independently O, S, N,NH or NH₁₈.

The aryl groups can be independently mono or multiply substituted withcyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl,alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl,alkylmercaptanyl, alkyl sulfonyl, aminosulfonyl, alkylaminosulfonyl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl,and/or other small substitution groups. In some embodiments, the smallsubstitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃, CH₂F,CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt,O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesulfonyl, Ph,benzyl, formyl, and acetyl.

In some embodiments, D₁ is an aryl, or a carbocycle.

In some embodiments, R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, and R₂₀ are independently: cyano, halogen,hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branchedhalogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl,alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl,branched halogenated alkylcarbonyl, arylcarbonyl or alkoxycarbonyl. Insome embodiments, R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₈, R₁₉, and R₂₀ are independently F, Cl, Br, CH₃, CH₂CH₃,CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt,O-i-Pr, methoxycarbonyl, phenyl, benzyl, formyl or acetyl, whenever theresulting structure is stable.

In some embodiments, R₁ and R₂, R₅ and R₆, R₇ and R₈, R₉ and R₁₀, R₁₁and R₁₂, R₁₃ and R₁₄, R₁₅ and R₁₆, R₁₉ and R₂₀, or R₁₅ and R₁₉ can forma monocycle.

In some embodiments, Me is methyl; Et is ethyl; i-Pr is i-propyl; t-Buis t-butyl; Ph is phenyl.

In some embodiments, the following compounds can be excluded from thegenus of compounds:2-[({2-[2-Ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol;2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol;{2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4yl]ethyl}[(4-methoxyphenyl)methyl]amine;{2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1R)-1-phenylethyl]amine;{2-[(4S*, 4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1S)-1-phenylethyl]amine;Benzyl({2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl})amine;2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol;Benzyl[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine;{2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine;[(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine;{2-[4-(4-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}(1-phenylethyl)amine;[(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amine;Benzyl({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl]amine};[(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine;4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline;Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}amine;{2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}(1-phenylethyl)amine;[2-(2,2-Dimethyl-4-phenyloxan-4-yl)ethyl][(4-methoxyphenyl)methyl]amine;{2-[4-(4-Fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine;[(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine

This application also describes compounds having the formula of FormulaII-1 and II2:

wherein A₂ is CH₂, CHR₅, CR₅R₆; A₄ is CH₂, CHR₉, CR₉R₁₀ or a cycle ofthe formula C(CH₂)_(n), where n=2-5.

Further, in some embodiments, R₅ R₆, R₉, and R₁₀ are independently CH₃,CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, orphenyl. Further, R₅ and R₆, or R₉ and R₁₀ can form a monocycliccarbocycle.

In some embodiments, A₂ and A₄ can be connected by a carbon bridge. Thisbridge can be —CH₂— or —CH₂CH₂—.

Further, in some embodiments, B₃ is selected from the following: H,alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branchedalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl. In someembodiments, B₃ is C₁-C₅ alkyl. In some embodiments, B₃ is H.

Further, in some embodiments, B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂,CHR₁₉, CR₁₉R₂₀ or CO. Further, R₁₉ and R₂₀ can form a monocycle of theformula (CH₂)_(n), where n=2-4. B₅ is alkyl, branched alkyl, carbocycle,carbocycle-substituted alkyl, aryl or arylalkyl.

In some embodiments, Further D₁ is an aryl. Examples of the aryl groupsare shown above.

Each aryl group can be independently mono or multiply substituted withF, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr,t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl,Ph, benzyl, formyl, or acetyl. That is, each aryl group may be multiplysubstituted with the same substituent (i.e., 2 chloro groups) or just bemultiply substituted, albeit with different groups (e.g. an aryl groupwith 1 chloro and 1 methyl group would be considered multiplysubstituted).

This application also provides compounds having the structure of FormulaIII:

wherein A₂ is CH₂, CHR₅ or CR₅R₆; A₄ is CH₂, CHR₉, CR₉R₁₀ or a cycle ofthe formula C(CH₂)_(n), where n=2-5.

Further R₅, R₆, R₉, and R₁₀ are independently CH₃, CH₂CH₃, CH₂F, CHF₂,CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. R₅ and R₆, or R₉and R₁₀ can form a monocyclic carbocycle.

A₂ and A₄ can be connected by a carbon bridge. The bridge can be —CH₂—or —CH₂CH₂—.

Further B₃ is selected from H, alkyl, branched alkyl, aryl, arylalkyl,alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl oralkyl sulfonyl.

Further B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀ or CO.Further, R₁₉ and R₂₀ can form a monocycle of the formula (CH₂)_(n),where n=2-4. B₅ is alkyl, branched alkyl, carbocycle,carbocycle-substituted alkyl, aryl or arylalkyl.

Further D₁ is an aryl. Examples of the aryl groups are shown above.

The aryl groups can be mono or multiply substituted with F, Cl, Br, CH₃,CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH,OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, Ph, benzyl,formyl, or acetyl.

This application also provides compounds having the formula of FormulaIV-1, IV-2, or IV-3, V, or VI:

wherein R₂₁ and R₂₂ are, independently, H or CH₃; A₄ is CH₂, CR₉R₁₀ or acycle of the formula C(CH₂)_(n), where n=2-5.

Further R₉ and R₁₀ are independently CH₃ or CH₂CH₃.

Further B₃ is H, C₁-C₆ alkyl or branched alkyl.

Further B₄ is null, C₁-C₆ alkyl, CH₂, CH₂CH₂, or —CHCH₃.

B₅ is —(CH₂)_(n)CH₃, where n=2-3, —C(CH₃)₃, cyclohexyl, cyclopentyl,aryl or arylalkyl.

In some embodiments, the aryl group is selected from the list below:

Each aryl groups can be mono or multiply substituted with, for example,F, I, Cl, Br, CH₃, CN, OH, OMe, OEt, OCF₃, CF₃, or methanesulfonyl.

Further, in some embodiments, D₁ is a phenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl which can be independently mono or multiply substituted withF, Cl, Br, OCF₃, CF₃, or CH₃.

This application also provides compounds having the structure of FormulaV-1, V-2, V-3, VI-1, VI-2, or VI-3:

wherein D₁ is an aryl; B₅ is an aryl or carbocycle.

In some embodiments, each aryl group is independently selected from thelist below:

In some embodiments, each aryl group is independently mono or multiplysubstituted. In some embodiments, each aryl group can be independentlymono or multiply substituted with I, F, Cl, Br, CH₃, CN, OH, OMe, OEt,OCF₃, CF₃, or methane sulfonyl. Further, in some embodiments, thecarbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

In some embodiments, D₁ is an optionally mono or multiply substitutedaryl. In some embodiments, B₅ is an optionally mono or multiplysubstituted aryl or carbocycle. In some embodiments, D₁ or B₅ isindependently selected from the group consisting of:

wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

In some embodiments, D₁ is optionally mono or multiply substitutedphenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, D₁ isoptionally substituted with one or more of F, Cl, Br, I, OCF₃, CH₃, andCF₃. In some embodiments, D₁ is not substituted.

In some embodiments, B₅ is optionally mono or multiply substituted

In some embodiments, B₅ is substituted with one or more of Cl, Br, F, I,OMe, CN, CH₃, methanesulfonyl, and CF₃. In some embodiments, B₅ issubstituted with two or more of Cl, Br, F, I, OMe, CN, CH₃, CF₃, andmethanesulfonyl, or a combination thereof. That is B₅ can have two ormore substituents but not all of the plurality of substituents needs tobe the same.

In some embodiments, compounds having structures of Formula VII-1,VII-2., or VII-3

are provided, wherein D₁ is an optionally substituted heteroaryl oraryl, B₃ is H or alkyl, B₅ is an optionally substituted aryl orheteroaryl, and R₂₆ and R₂₇ are each hydrogen or an isotope thereof. Insome embodiments, R₂₆ and R₂₇ are deuterium. In some embodiments, R₂₆ orR₂₇ are independently alkyl. In some embodiments, B₃ is C₁-C₅ alkyl.

In some embodiments, the compound has a structure of Formula VIII or anenantiomer thereof

wherein D1 is an optionally substituted heteroaryl or aryl, B3 is H oralkyl, B5 is an optionally substituted aryl or heteroaryl, and R26 andR27 are each hydrogen or an isotope thereof. In some embodiments, R26and R27 are deuterium. In some embodiments, R26 or R27 are independentlyalkyl. A4 is as described herein. In some embodiments, B3 is C1-C5alkyl. In some embodiments, the enantiomer is the R or S enantiomer atthe carbon that is connected to D1.

In some embodiments, a compound has the structure of Formula IX or anenantiomer thereof

In some embodiments, the enantiomer is the R or S enantiomer at thecarbon that is connected to D₁.

In some embodiments, a compound has the structure of Formula X or anenantiomer thereof

In some embodiments, the enantiomer is the R or S enantiomer at thecarbon that is connected to D1.

In some embodiments of the structures described herein, D1 is anoptionally substituted pyridyl group or phenyl group. In someembodiments, D1 is an optionally substituted 2-pyridyl, 3-pyridyl, or4-pyridyl group or phenyl group. In some embodiments, D1 is optionallysubstituted with one or more of, H, OH, alkyl alcohol, halo, alkyl,amine, amide, cyano, alkoxy, haloalkyl, or alkylsulfonyl. In someembodiments, D1 is optionally substituted with one or more of H, OH, Cl,Br, F, I, OMe, CN, CH₃, CF₃.

In some embodiments of the structures described herein, B₅ is anoptionally substituted thiophene group. In some embodiments, B₅ issubstituted with an alkoxy group. In some embodiments, B₅ is substitutedwith a C₁-C₅ alkoxy group. In some embodiments, B₅ is substituted with amethoxy group. In some embodiments, B₅ is

In some embodiments, B₅ is

wherein R₂₃, R₂₄, and R₃₀ are each independently null, H, OH, cycle,aryl, branched or unbranched alkyl alcohol, halo, branched or unbranchedalkyl, amine, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite,alkylsulfanyl, and R₂₅ is H or alkyl. In some embodiments, R₂₃ and R₂₄together form a aryl or cycle that is attached to one or more of theatoms of B₅. R₂₃ R₂₄, and R₃₀ can also be further substituted. In someembodiments, R₂₃, R₂₄, and R₃₀ are each independently H, NH₂, OH, Cl,Br, F, I, OMe, CN, CH₃, phenyl, C₃-C₆ carbocycle, methanesulfonyl, CF₃,

wherein R₂₉ is H or an alkyl. In some embodiments, R₂₉ is a C₁-C₆ alkyl.In some embodiments, one of R₂₃, R₂₄, and R₃₀ is H. In some embodiments,at least one of R₂₃, R₂₄, and R₃₀ is H. In some embodiments, two of R₂₃,R₂₄, and R₃₀ are H.

The following compounds and others described herein have agonistactivity for OR mediated signaltransduction:[(4-chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amine;[(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine;2-[({2-[2-ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol;[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl][(2-fluorophenyl)methyl]amine;4-[{2-[4-(2-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline;2-[({2-[2-ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol;[(3-methoxythiophene-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine.Other examples include the compounds, and pharmaceutically acceptablesalts thereof, described herein.

In some embodiments, compounds, such as the ones described herein areprovided. In some embodiments, a compound selected from the compoundsdescribed in the Examples is provided. The compounds can be used in anyof the methods described herein, including, but not limited to, treatingpain. For example, the compounds can be used for treating or reversinghyperalgesia, induced hyperalgesia, decreasing nociceptivesensitization, and the like. The compounds can be also be used in thepreparation of a medicament for the same. In some embodiments, uses ofthe compounds for treating pain, treating or reversing hyperalgesia,induced hyperalgesia, decreasing nociceptive sensitization, and thelike, are provided.

Thus, the application provides methods of generating agonist activity inOR mediated signal transduction through administration of one or more ofthe above recited compounds to a subject or subject in need thereof.

Various atoms in the compositions described herein can be isotopes thatoccur at lower frequency. Hydrogen can be replaced at any position inthe compositions described herein with deuterium. Optionally, hydrogencan also be replaced with tritium. Carbon (¹²C) can be replaced at anyposition in the compositions described herein with ¹³C or ¹⁴C. Nitrogen(¹⁴N) can be replaced with ¹⁵N. Oxygen (¹⁶O) can be replaced at anyposition in the compositions described herein with ¹⁷O or ¹⁸O. Sulfur(³²S) can be replaced at any position in the compositions describedherein with ³³S, ³⁴S or ³⁶S. Chlorine (³⁵Cl) can be replaced at anyposition in the compositions described herein with ³⁷Cl. Bromine (⁷⁹Br)can be replaced at any position in the compositions described hereinwith ⁸¹Br.

Selected compounds described herein are agonists and antagonists ofOpioid Receptors (ORs). The ability of the compounds to stimulate ORmediated signaling may be measured using any assay known in the art todetect OR mediated signaling or OR activity, or the absence of suchsignaling/activity. “OR activity” refers to the ability of an OR totransduce a signal. Such activity can be measured, e.g., in aheterologous cell, by coupling an OR (or a chimeric OR) to a downstreameffector such as adenylate cyclase.

A “natural ligand-induced activity” as used herein, refers to activationof the OR by a natural ligand of the OR. Activity can be assessed usingany number of endpoints to measure OR activity.

Generally, assays for testing compounds that modulate OR-mediated signaltransduction include the determination of any parameter that isindirectly or directly under the influence of a OR, e.g., a functional,physical, or chemical effect.

Samples or assays comprising ORs that are treated with a potentialactivator, inhibitor, or modulator are compared to control sampleswithout the inhibitor, activator, or modulator to examine the extent ofinhibition. Control samples (untreated with inhibitors) are assigned arelative OR activity value of 100%. Inhibition of an OR is achieved whenthe OR activity value relative to the control is about 80%, 50%, or 25%.Activation of an OR is achieved when the OR activity value relative tothe control (untreated with activators) is 110%, 150%, 200-500% (i.e.,two to five fold higher relative to the control) or, 1000-3000% orhigher.

The effects of the compounds upon the function of an OR can be measuredby examining any of the parameters described above. Any suitablephysiological change that affects OR activity can be used to assess theinfluence of a compound on the ORs and natural ligand-mediated ORactivity. When the functional consequences are determined using intactcells or animals, one can also measure a variety of effects such aschanges in intracellular second messengers such as cAMP.

Modulators of OR activity are tested using OR polypeptides as describedabove, either recombinant or naturally occurring. The protein can beisolated, expressed in a cell, expressed in a membrane derived from acell, expressed in tissue or in an animal. For example, neuronal cells,cells of the immune system, transformed cells, or membranes can be usedto test the GPCR polypeptides described above. Modulation is testedusing one of the in vitro or in vivo assays described herein. Signaltransduction can also be examined in vitro with soluble or solid statereactions, using a chimeric molecule such as an extracellular domain ofa receptor covalently linked to a heterologous signal transductiondomain, or a heterologous extracellular domain covalently linked to thetransmembrane and or cytoplasmic domain of a receptor. Furthermore,ligand-binding domains of the protein of interest can be used in vitroin soluble or solid state reactions to assay for ligand binding.

Ligand binding to an OR, a domain, or chimeric protein can be tested ina number of formats. Binding can be performed in solution, in a bilayermembrane, attached to a solid phase, in a lipid monolayer, or invesicles. Typically, in an assay described herein, the binding of thenatural ligand to its receptor is measured in the presence of acandidate modulator. Alternatively, the binding of the candidatemodulator may be measured in the presence of the natural ligand. Often,competitive assays that measure the ability of a compound to competewith binding of the natural ligand to the receptor are used. Binding canbe tested by measuring, e.g., changes in spectroscopic characteristics(e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g.,shape) changes, or changes in chromatographic or solubility properties.

Modulators may also be identified using assays involving β-arrestinrecruitment. β-arrestin serves as a regulatory protein that isdistributed throughout the cytoplasm in unactivated cells. Ligandbinding to an appropriate OR is associated with redistribution ofβ-arrestin from the cytoplasm to the cell surface, where it associateswith the OR. Thus, receptor activation and the effect of candidatemodulators on ligand-induced receptor activation, can be assessed bymonitoring β-arrestin recruitment to the cell surface. This isfrequently performed by transfecting a labeled β-arrestin fusion protein(e.g., β-arrestin-green fluorescent protein (GFP)) into cells andmonitoring its distribution using confocal microscopy (see, e.g.,Groarke et al., J. Biol. Chem. 274(33):23263 69 (1999)).

Another technology that can be used to evaluate OR-protein interactionsin living cells involves bioluminescence resonance energy transfer(BRET). A detailed discussion regarding BRET can be found in Kroeger etal., J. Biol. Chem., 276(16):12736 43 (2001).

Other assays can involve determining the activity of receptors which,when activated by ligand binding, result in a change in the level ofintracellular cyclic nucleotides, e.g., cAMP, by activating orinhibiting downstream effectors such as adenylate cyclase. Changes inintracellular cAMP can be measured using immunoassays. The methoddescribed in Offermanns & Simon, J. Biol. Chem. 270:15175 15180 (1995)may be used to determine the level of cAMP. Also, the method describedin Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11:159 164(1994) may be used to determine the level of cGMP. Further, an assay kitfor measuring cAMP a is described in U.S. Pat. No. 4,115,538, hereinincorporated by reference.

Transcription levels can be measured to assess the effects of a testcompound on ligand-induced signal transduction. A host cell containingthe protein of interest is contacted with a test compound in thepresence of the natural ligand for a sufficient time to effect anyinteractions, and then the level of gene expression is measured. Theamount of time to effect such interactions may be empiricallydetermined, such as by running a time course and measuring the level oftranscription as a function of time. The amount of transcription may bemeasured by using any method known to those of skill in the art to besuitable. For example, mRNA expression of the protein of interest may bedetected using northern blots or their polypeptide products may beidentified using immunoassays. Alternatively, transcription based assaysusing reporter genes may be used as described in U.S. Pat. No.5,436,128, herein incorporated by reference. The reporter genes can be,e.g., chloramphenicol acetyltransferase, firefly luciferase, bacterialluciferase, β-galactosidase and alkaline phosphatase. Furthermore, theprotein of interest can be used as an indirect reporter via attachmentto a second reporter such as green fluorescent protein (see, e.g.,Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).

The amount of transcription is then compared to the amount oftranscription in either the same cell in the absence of the testcompound, or it may be compared with the amount of transcription in asubstantially identical cell that lacks the protein of interest. Asubstantially identical cell may be derived from the same cells fromwhich the recombinant cell was prepared but which had not been modifiedby introduction of heterologous DNA. Any difference in the amount oftranscription indicates that the test compound has in some manneraltered the activity of the protein of interest.

Pharmaceutical Compositions/Formulations

Pharmaceutical compositions can be formulated by standard techniquesusing one or more physiologically acceptable carriers or excipients. Theformulations may contain a buffer and/or a preservative. The compoundsand their physiologically acceptable salts and solvates can beformulated for administration by any suitable route, including viainhalation, topically, nasally, orally, parenterally (e.g.,intravenously, intraperitoneally, intravesically or intrathecally) orrectally in a vehicle comprising one or more pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard biological practice.

Pharmaceutical compositions can include effective amounts of one or morecompound(s) described herein together with, for example,pharmaceutically acceptable diluents, preservatives, solubilizers,emulsifiers, adjuvants and/or other carriers. Such compositions mayinclude diluents of various buffer content (e.g., TRIS or other amines,carbonates, phosphates, amino acids, for example, glycinamidehydrochloride (especially in the physiological pH range),N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc.or TRIS-HCl or acetate), pH and ionic strength; additives such asdetergents and solubilizing agents (e.g., surfactants such as Pluronics,Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such aspolyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol,benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugarssuch as sucrose, lactose, mannitol, polymers such aspolyvinylpyrrolidones or dextran, etc.); and/or incorporation of thematerial into particulate preparations of polymeric compounds such aspolylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronicacid may also be used. Such compositions can be employed to influencethe physical state, stability, rate of in vivo release, and rate of invivo clearance of a compound described herein. See, e.g., Remington'sPharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton,Pa. 18042) pages 1435-1712 which are herein incorporated by reference.The compositions can, for example, be prepared in liquid form, or can bein dried powder, such as lyophilized form. Particular methods ofadministering such compositions are described infra.

Where a buffer is to be included in the formulations described herein,the buffer can be selected from sodium acetate, sodium carbonate,citrate, glycylglycine, histidine, glycine, lysine, arginine, sodiumdihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, andtris(hydroxymethyl)-aminomethane, or mixtures thereof. The buffer canalso be glycylglycine, sodium dihydrogen phosphate, disodium hydrogenphosphate, and sodium phosphate or mixtures thereof.

Where a pharmaceutically acceptable preservative is to be included in aformulation of one of the compounds described herein, the preservativecan be selected from phenol, m-cresol, methyl p-hydroxybenzoate, propylp-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate,2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, ormixtures thereof. The preservative can also be phenol or m-cresol.

The preservative is present in a concentration from about 0.1 mg/ml toabout 50 mg/ml, in a concentration from about 0.1 mg/ml to about 25mg/ml, or in a concentration from about 0.1 mg/ml to about 10 mg/ml.

The use of a preservative in pharmaceutical compositions is well-knownto the skilled person. For convenience reference is made to Remington:The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation may further comprise a chelating agent where thechelating agent may be selected from salts of ethylenediaminetetraaceticacid (EDTA), citric acid, and aspartic acid, and mixtures thereof.

The chelating agent can be present in a concentration from 0.1 mg/ml to5 mg/ml, from 0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.

The use of a chelating agent in pharmaceutical compositions iswell-known to the skilled person. For convenience reference is made toRemington: The Science and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further comprise astabilizer selected from high molecular weight polymers and lowmolecular compounds where such stabilizers include, but are not limitedto, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA),polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g.sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine,isoleucine, aspartic acid, tryptophan, and threonine or any mixturethereof. The stabilizer can also be L-histidine, imidazole or arginine.

The high molecular weight polymer can be present in a concentration from0.1 mg/ml to 50 mg/m, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30mg/ml to 50 mg/ml.

The low molecular weight compound can be present in a concentration from0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30mg/ml to 50 mg/ml.

The use of a stabilizer in pharmaceutical compositions is well-known tothe skilled person. For convenience reference is made to Remington: TheScience and Practice of Pharmacy, 19th edition, 1995.

The formulation of the compounds described herein may further include asurfactant. IN some embodiments, the surfactant may be selected from adetergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylatedmonoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylenederivatives such as alkylated and alkoxylated derivatives (tweens, e.g.Tween-20, or Tween-80), monoglycerides or ethoxylated derivativesthereof, diglycerides or polyoxyethylene derivatives thereof, glycerol,cholic acid or derivatives thereof, lecithins, alcohols andphospholipids, glycerophospholipids (lecithins, kephalins, phosphatidylserine), glyceroglycolipids (galactopyransoide), sphingophospholipids(sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS(docusate sodium, docusate calcium, docusate potassium, SDS (sodiumdodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidicacid, sodium caprylate, bile acids and salts thereof and glycine ortaurine conjugates, ursodeoxycholic acid, sodium cholate, sodiumdeoxycholate, sodium taurocholate, sodium glycocholate,N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic(alkyl-aryl-sulphonates) monovalent surfactants, palmitoyllysophosphatidyl-L-serine, lysophospholipids (e.g.1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine orthreonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkylether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g.lauroyl and myristoyl derivatives of lysophosphatidylcholine,dipalmitoylphosphatidylcholine, and modifications of the polar headgroup, that is cholines, ethanolamines, phosphatidic acid, serines,threonines, glycerol, inositol, and the positively charged DODAC, DOTMA,DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine,zwitterionic surfactants (e.g.N-alkyl-N,N-dimethylammonio-1-propanesulfonates,3-cholamido-1-propyldimethylammonio-1-propanesulfonate,dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egglysolecithin), cationic surfactants (quarternary ammonium bases) (e.g.cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionicsurfactants, polyethyleneoxide/polypropyleneoxide block copolymers(Pluronics/Tetronics, Triton X-100, Dodecyl β-D-glucopyranoside) orpolymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acidderivatives—(e.g. sodium tauro-dihydrofusidate etc.), long-chain fattyacids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid),acylcarnitines and derivatives, N_(α)-acylated derivatives of lysine,arginine or histidine, or side-chain acylated derivatives of lysine orarginine, N_(α)-acylated derivatives of dipeptides comprising anycombination of lysine, arginine or histidine and a neutral or acidicamino acid, N_(α)-acylated derivative of a tripeptide comprising anycombination of a neutral amino acid and two charged amino acids, or thesurfactant may be selected from the group of imidazoline derivatives, ormixtures thereof.

The use of a surfactant in pharmaceutical compositions is well-known tothe skilled person. For convenience reference is made to Remington: TheScience and Practice of Pharmacy, 19th edition, 1995.

Pharmaceutically acceptable sweeteners can be part of the formulation ofthe compounds described herein. Pharmaceutically acceptable sweetenersinclude at least one intense sweetener such as saccharin, sodium orcalcium saccharin, aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), saccharin, sodium orcalcium saccharin, and optionally a bulk sweetener such as sorbitol,mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenatedglucose syrup, xylitol, caramel, and honey.

Intense sweeteners are conveniently employed in low concentrations. Forexample, in the case of sodium saccharin, the concentration may rangefrom 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, or is about 0.06% in the low-dosage formulations and about0.08% in the high-dosage ones. The bulk sweetener can effectively beused in larger quantities ranging from about 10% to about 35%, or fromabout 10% to 15% (w/v).

The formulations of the compounds described herein may be prepared byconventional techniques, e.g. as described in Remington's PharmaceuticalSciences, 1985 or in Remington: The Science and Practice of Pharmacy,19th edition, 1995, where such conventional techniques of thepharmaceutical industry involve dissolving and mixing the ingredients asappropriate to give the desired end product.

The phrase “pharmaceutically acceptable” or “therapeutically acceptable”refers to molecular entities and compositions that are physiologicallytolerable and preferably do not typically produce an allergic or similaruntoward reaction, such as gastric upset, dizziness and the like, whenadministered to a human. As used herein, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or aState government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia (e.g., Remington's Pharmaceutical Sciences, MackPublishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and moreparticularly in humans.

Administration of the compounds described herein may be carried outusing any method known in the art. For example, administration may betransdermal, parenteral, intravenous, intra-arterial, subcutaneous,intramuscular, intracranial, intraorbital, ophthalmic, intraventricular,intracapsular, intraspinal, intracisternal, intraperitoneal,intracerebroventricular, intrathecal, intranasal, aerosol, bysuppositories, or oral administration. A pharmaceutical composition ofthe compounds described herein can be for administration for injection,or for oral, pulmonary, nasal, transdermal, ocular administration.

For oral administration, the pharmaceutical composition of the compoundsdescribed herein can be formulated in unit dosage forms such as capsulesor tablets. The tablets or capsules may be prepared by conventionalmeans with pharmaceutically acceptable excipients, including bindingagents, for example, pregelatinised maize starch, polyvinylpyrrolidone,or hydroxypropyl methylcellulose; fillers, for example, lactose,microcrystalline cellulose, or calcium hydrogen phosphate; lubricants,for example, magnesium stearate, talc, or silica; disintegrants, forexample, potato starch or sodium starch glycolate; or wetting agents,for example, sodium lauryl sulphate. Tablets can be coated by methodswell known in the art. Liquid preparations for oral administration cantake the form of, for example, solutions, syrups, or suspensions, orthey can be presented as a dry product for constitution with water orother suitable vehicle before use. Such liquid preparations can beprepared by conventional means with pharmaceutically acceptableadditives, for example, suspending agents, for example, sorbitol syrup,cellulose derivatives, or hydrogenated edible fats; emulsifying agents,for example, lecithin or acacia; non-aqueous vehicles, for example,almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils;and preservatives, for example, methyl or propyl-p-hydroxybenzoates orsorbic acid. The preparations can also contain buffer salts, flavoring,coloring, and/or sweetening agents as appropriate. If desired,preparations for oral administration can be suitably formulated to givecontrolled release of the active compound.

For topical administration, the pharmaceutical composition of thecompounds described herein can be formulated in a pharmaceuticallyacceptable vehicle containing 0.1 to 10 percent, or 0.5 to 5 percent, ofthe active compound(s). Such formulations can be in the form of a cream,lotion, sublingual tablet, aerosols and/or emulsions and can be includedin a transdermal or buccal patch of the matrix or reservoir type as areconventional in the art for this purpose.

For parenteral administration, the compounds described herein areadministered by either intravenous, subcutaneous, or intramuscularinjection, in compositions with pharmaceutically acceptable vehicles orcarriers. The compounds can be formulated for parenteral administrationby injection, for example, by bolus injection or continuous infusion.Formulations for injection can be presented in unit dosage form, forexample, in ampoules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents, for example, suspending, stabilizing, and/ordispersing agents. Alternatively, the active ingredient can be in powderform for constitution with a suitable vehicle, for example, sterilepyrogen-free water, before use.

For administration by injection, the compound(s) can be used in solutionin a sterile aqueous vehicle which may also contain other solutes suchas buffers or preservatives as well as sufficient quantities ofpharmaceutically acceptable salts or of glucose to make the solutionisotonic. The pharmaceutical compositions of the compounds describedherein may be formulated with a pharmaceutically acceptable carrier toprovide sterile solutions or suspensions for injectable administration.Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspensions in liquid prior to injection or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, or thelike. In addition, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like. If desired,absorption enhancing preparations (e.g., liposomes) may be utilized.Suitable pharmaceutical carriers are described in “Remington'spharmaceutical Sciences” by E. W. Martin.

For administration by inhalation, the compounds may be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, forexample, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase, for example, lactose or starch. For intranasal administration thecompounds described herein may be used, for example, as a liquid spray,as a powder or in the form of drops.

The compounds can also be formulated in rectal compositions, forexample, suppositories or retention enemas, for example, containingconventional suppository bases, for example, cocoa butter or otherglycerides.

Furthermore, the compounds can be formulated as a depot preparation.Such long-acting formulations can be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The compositions can, if desired, be presented in a pack or dispenserdevice that can contain one or more unit dosage forms containing theactive ingredient. The pack can, for example, comprise metal or plasticfoil, for example, a blister pack. The pack or dispenser device can beaccompanied by instructions for administration.

The compounds described herein also include derivatives referred to asprodrugs, which can be prepared by modifying functional groups presentin the compounds in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent compounds.Examples of prodrugs include compounds of the invention as describedherein that contain one or more molecular moieties appended to ahydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and thatwhen administered to a patient, cleaves in vivo to form the freehydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examplesof prodrugs include, but are not limited to, acetate, formate andbenzoate derivatives of alcohol and amine functional groups in thecompounds of the invention. Preparation and use of prodrugs is discussedin T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencein their entireties.

Dosages

The compounds described herein may be administered to a patient attherapeutically effective doses to prevent, treat, or control one ormore diseases and disorders mediated, in whole or in part, by anOR-ligand interaction. Pharmaceutical compositions comprising one ormore of compounds described herein may be administered to a patient inan amount sufficient to elicit an effective protective or therapeuticresponse in the patient. An amount adequate to accomplish this isdefined as “therapeutically effective dose.” The dose will be determinedby the efficacy of the particular compound employed and the condition ofthe subject, as well as the body weight or surface area of the area tobe treated. The size of the dose also will be determined by theexistence, nature, and extent of any adverse effects that accompany theadministration of a particular compound or vector in a particularsubject.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, for example, by determining the LD50 (the dose lethal to 50% ofthe population) and the ED50 (the dose therapeutically effective in 50%of the population). The dose ratio between toxic and therapeutic effectsis the therapeutic index and can be expressed as the ratio, LD50/ED50.In some embodiments, compounds that exhibit large therapeutic indicesare used. While compounds that exhibit toxic side effects can be used,care should be taken to design a delivery system that targets suchcompounds to the site of affected tissue to minimize potential damage tonormal cells and, thereby, reduce side effects.

The data obtained from cell culture assays and animal studies can beused to formulate a dosage range for use in humans. In some embodiments,the dosage of such compounds lies within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration. For any compound describedherein, the therapeutically effective dose can be estimated initiallyfrom cell culture assays. A dose can be formulated in animal models toachieve a circulating plasma concentration range that includes the IC50(the concentration of the test compound that achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsin plasma can be measured, for example, by high performance liquidchromatography (HPLC). In general, the dose equivalent of a modulator isfrom about 1 ng/kg to 10 mg/kg for a typical subject.

The amount and frequency of administration of the compounds describedherein and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition. In general it is contemplated that aneffective amount would be from 0.001 mg/kg to 10 mg/kg body weight, andin particular from 0.01 mg/kg to 1 mg/kg body weight. It may beappropriate to administer the required dose as two, three, four or moresub-doses at appropriate intervals throughout the day. Said sub-dosesmay be formulated as unit dosage forms, for example, containing 0.01 to500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unitdosage form.

In some embodiments, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose. The quantityof active compound in a unit dose of preparation may be varied oradjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg toabout 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mgto about 250 mg, according to the particular application. The actualdosage employed may be varied depending upon the requirements of thepatient and the severity of the condition being treated. Determinationof the proper dosage regimen for a particular situation is within theskill of the art. For convenience, the total dosage may be divided andadministered in portions during the day as required.

In some embodiments, one or more compounds described herein areadministered with another compound. The administration may besequentially or concurrently. The combination may be in the same dosageform or administered as separate doses. In some embodiments, the anothercompound is another analgesic or pain reliever. In some embodiments, theanother compound is a non-opioid analgesic. Examples of usefulnon-opioid analgesics include, but are not limited to, non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicyl salicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9.sup.th ed 1996); andGlen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19.sup.th ed. 1995), which are hereby incorporated byreference in their entireties.

The compounds described herein can also be administered Cox-IIinhibitors. Examples of useful Cox-II inhibitors and 5-lipoxygenaseinhibitors, as well as combinations thereof, are described in U.S. Pat.No. 6,136,839, which is hereby incorporated by reference in itsentirety. Examples of Cox-II inhibitors include, but are not limited to,rofecoxib and celecoxib.

The compounds described herein can also be administered withantimigraine agents. Examples of useful antimigraine agents include, butare not limited to, alpiropride, bromocriptine, dihydroergotamine,dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot,ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride,lomerizine, methylergonovine, methysergide, metoprolol, naratriptan,oxetorone, pizotyline, propranolol, risperidone, rizatriptan,sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.

The compounds described herein can also be administered withanti-constipation agents. Examples of anti-constipation agents include,but are not limited to, laxatives or stool softners. Examples ofanti-constipation agents include, but are not limited to, be docusate,poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose,polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesiumhydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium biphosphate or any combination thereof.

Medical Use

The compositions described herein may be useful for treating pain orpain associated disorders. The compositions described herein may beuseful for treating immune dysfunction, inflammation, esophageal reflux,neurological and psychiatric conditions, urological and reproductiveconditions, medicaments for drug and alcohol abuse, agents for treatinggastritis and diarrhea, cardiovascular agents and agents for thetreatment of respiratory diseases and cough.

In some embodiments, methods of treating pain are provided. In someembodiments, one or more compound described herein are administered to asubject to treat the pain. In some embodiments, the pain can bepost-operative pain. In some embodiments, the pain is caused by cancer.In some embodiments, the pain is neuropathic pain. In some embodiments,the pain is caused by trauma, such as but not limited to, blunt forcetrauma. In some embodiments, the pain is caused by inflammation.

In some embodiments, the one or more compounds can used for treating orreversing hyperalgesia. Accordingly, in some embodiments, methods oftreating or reversing hyperalgesia are provided. In some embodiments,the methods comprise administering to a subject one or more compoundsdescribed herein, or pharmaceutically acceptable salts thereof. In someembodiments, a pharmaceutical composition comprising the one or morecompounds, or pharmaceutically acceptable salts thereof areadministered. As used herein, hyprealgesia refers to a condition where asubject has an increased sensitivity to pain. The increase sensitivitycan occur at the site of a previous injury or pain sensation or can beat a different site. In some embodiments, the hyperalgesia is diffusehyperlagesia (i.e. in more than one site on the subject) or is focal,(i.e. at a discrete site on the subject). In some embodiments, thesubject has been administered a first opioid prior to being administeredthe one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the hyperalgesia is opioid induced hyperalgesia,which can also be referred to as opioid-induced abnormal painsensitivity or paradoxical hyperalgesia, which is described as acondition that results from the use of opioids. For example, individualstaking opioids can develop an increasing sensitivity to noxious stimuli,even evolving a painful response to previously non-noxious stimuli(allodynia). This is a result of the subject being exposed to opioids.Opioid induced hyperalgesia (OIH) is distinct and different from what isknown as “tolerance.” Without being bound to any particular theory,tolerance is due to desensitization of antinociceptive mechanismswhereas OIH is due to sensitization of pronociceptive mechanisms.Therefore, where opioid tolerance is identified as a condition in asubject the tolerance can be minimized by increasing the dose of theopioid. In contrast, increasing the dose of an opioid in a subjectsuffering from OIH will only worsen the condition. In some embodiments,the compounds described herein are used for the preparation of amedicament for treating hyperalgesia or opioid induced hyperalgesia.

In some embodiments, the opioid induced hyperalgesia is morphine,oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil,remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/orheroin induced hyperalgesia. In some embodiments, the OIH is induced bya combination of more than one opioid. In some embodiments, the OIH ismorphine induced OIH. In some embodiments, the OIH is oxycodone inducedOIH. In some embodiments, the OIH is hydrocodone induced OIH. In someembodiments, the OIH is hydromorphone induced OIH. In some embodiments,the OIH is fentanyl induced OIH. In some embodiments, the OIH isbuprenorphine induced OIH. In some embodiments, the OIH is heroininduced OIH.

In some embodiments, methods of decreasing nociceptive sensitization ina subject are provided. In some embodiments, the methods compriseadministering to a subject one or more compounds described herein, orpharmaceutically acceptable salts thereof. In some embodiments, apharmaceutical composition comprising the one or more compounds, orpharmaceutically acceptable salts thereof are administered. In someembodiments, the the subject has increased nociceptive sensitization. Insome embodiments, the nociceptive sensitization is induced by anothertherapeutic. In some embodiments, the nociceptive sensitization isopioid induced nociceptive sensitization. In some embodiments, theopioid induced nociceptive sensitization is morphine, oxycodone,hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil,remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/orheroin, or a pharmaceutically acceptable salt thereof, inducednociceptive sensitization.

In some embodiments, methods of treating pain in a subject are provided,wherein the method comprises administering an opioid agonist to thesubject until the opioid increases nociceptive sensitization in thesubject; and then administering to the subject with increasednociceptive sensitization one or more compounds described herein, or apharmaceutically acceptable salt thereof. In some embodiments, theopioid agonist is morphine, oxycodone, hydrocodone, hydromorphone,fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine,buprenorphine, methadone, and/or heroin, or pharmaceutically acceptablesalts thereof. In some embodiments, a pharmaceutical compositioncomprising the one or more compounds, or pharmaceutically acceptablesalts thereof are administered.

In some embodiments, methods of treating pain are provided, wherein themethods comprising administering administering an opioid agonist to thesubject; and then administering to the subject in the absence of theopioid and then administering to the subject one or more compoundsdescribed herein, or a pharmaceutically acceptable salt thereof. In someembodiments, the opioid agonist is morphine, oxycodone, hydrocodone,hydromorphone, fentanyl, meperidine, alfentanil, remifentanil,sufentanil, etorphine, buprenorphine, methadone, and/or heroin, orpharmaceutically acceptable salts thereof. In some embodiments, apharmaceutical composition comprising the one or more compounds, orpharmaceutically acceptable salts thereof are administered.

In some embodiments, the compounds are used in the preparation of amedicament for treating or reversing OIH, such as opioid induced OIH. Insome embodiments, uses of a compound, or pharmaceutically acceptablesalt thereof, for treating or reversing OIH are provided. Non-limitingexamples of opioid induced OIH are described above. In some embodiments,the compounds are used in the preparation of a medicament for treatingnociceptive sensitization. In some embodiments, uses of a compound, orpharmaceutically acceptable salt thereof, for treating nociceptivesensitization are provided. In some embodiments, the nociceptivesensitization is opioid induced. Non-limiting examples of opioid thatcan induce nociceptive sensitization are provided herein.

In some embodiments, the compound that is used in the methods, uses, orpreparation of a medicament is

or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is a compound as described in Examples 1-4, or apharmaceutically acceptable salt thereof.

In some embodiments,2-[({2-[2-Ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol;2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol;{2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4yl]ethyl}[(4-methoxyphenyl)methyl]amine;{2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1R)-1-phenylethyl]amine;{2-[(4S*, 4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1S)-1-phenylethyl]amine;Benzyl({2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amine;2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol;Benzyl[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine;{2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine;[(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine;{2-[4-(4-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}(1-phenylethyl)amine;[(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine;Benzyl({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl}amine;[(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl}amine;4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline;Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}amine;{2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}(1-phenylethyl)amine;[2-(2,2-Dimethyl-4-phenyloxan-4-yl)ethyl][(4-methoxyphenyl)methyl]amine;{2-[4-(4-Fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine;[(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine,or any combination thereof is not administered.

In some embodiments, a compound of formulaN-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine;N-((5-fluoropyridin-3-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine,or any stereoisomer thereof. For example, in some embodiments, thecompound is Compound 54, 135, 140, 150, 155, 215, 265, 270, 500, or anycombination thereof.

In some embodiments, the one or more compounds described herein can beadministered by any suitable route, including, but not limited to, viainhalation, topically, nasally, orally, parenterally (e.g.,intravenously, intraperitoneally, intravesically or intrathecally) orrectally in a vehicle comprising one or more pharmaceutically acceptablecarriers, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration andstandard practice.

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of thecompositions and compounds described herein, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only not intended tobe limiting. Other features and advantages of the compositions andcompounds described herein will be apparent from the following detaileddescription and claims.

As used herein, the phrase “in need thereof” means that the subject,animal or mammal has been identified as having a need for the particularmethod or treatment. In some embodiments, the identification can be byany means of diagnosis. In any of the methods and treatments describedherein, the subject, animal or mammal can be in need thereof. In someembodiments, the subject has been identified has having hyperalgesia,such as but not limited to, opioid induced hyperalgeisa. In someembodiments, the subject has been identified as having increasednociceptive sensitization. In some embodiments, the increasednociceptive sensitization is opioid induced nociceptive sensitization.

The general chemical terms used throughout have their usual meanings.For example, the term alkyl refers to a branched or unbranched saturatedhydrocarbon group. The term “n-alkyl” refers to an unbranched alkylgroup. The term “C_(x)-C_(y) alkyl” refers to an alkyl group having fromx to y carbon atoms, inclusively, in the branched or unbranchedhydrocarbon group. By way of illustration, but without limitation, theterm “C₁-C₄ alkyl” refers to a straight chain or branched hydrocarbonmoiety having from 1 to 4 carbon atoms, including methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Theterm “C₁-C₄ n-alkyl” refers to straight chain hydrocarbon moietieshaving from 1 to 4 carbon atoms including methyl, ethyl, n-propyl, andn-butyl. C_(x)-C_(y) x can be from 1 to 10 and y is from 2 to 20. Theterm “C₃-C₆ cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl. The term “C₃-C₇ cycloalkyl” also includes cycloheptyl.Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyllinker chain, as for example, but without limitation, cyclopropylmethyl,cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl,cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl,cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, andcyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group maybe optionally substituted, such as, but not limited to, as specifiedherein. In some embodiments, the alkyl is a C₁-C₃, C₁-C₄, C₁-C₆, C₄-C₆,or C₁-C₁₀ alkyl.

The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer toan alkyl group, phenyl group, benzyl group, or pyrimidinyl group,respectively, that is bonded through an oxygen atom. Each of thesegroups may be optionally substituted.

The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkylgroup, phenyl group, or benzyl group, respectively, that is bondedthrough a sulfur atom. Each of these groups may be optionallysubstituted.

The term “C₁-C₄ acyl” refers to a formyl group or a C₁-C₃ alkyl groupbonded through a carbonyl moiety. The term “C₁-C₄ alkoxycarbonyl” refersto a C₁-C₄ alkoxy group bonded through a carbonyl moiety.

The term “halo” refers to fluoro, chloro, bromo, or iodo. In someembodiments, the halo groups are fluoro, chloro, and bromo. In someembodiments, the halo groups are fluoro and chloro.

As used herein, “carbocycle” or “carbocyclic ring” is intended to mean,unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or12-membered monocyclic, bicyclic or tricyclic ring, any of which can besaturated, unsaturated (including partially and fully unsaturated), oraromatic. Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.As shown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when oneor more carbon atoms link two non-adjacent carbon atoms. In someembodiments, the bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring can also bepresent on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) andspiro rings are also included.

The term “heterocycle” is taken to mean a saturated or unsaturated 5- or6-membered ring containing from 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur, said ring optionally being benzofused.Exemplary heterocycles include furanyl, thiophenyl (thienyl), pyrrolyl,pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like. Benzofused heterocyclic rings includeisoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,benzofuranyl, benzothiophenyl, indolyl, and the like, all of which maybe optionally substituted, which also of course includes optionallysubstituted on the benzo ring when the heterocycle is benzofused.

The term “cycle” group is taken to mean a carbocylic ring, a carbocycleor a heterocarbocyle.

As used herein, the phrase a “cycle of the formula” refers to a ringthat can be formed with the variable referred to. For example, in thestructure

wherein A can be a cycle of the formula C(CH₂)_(n), where n=2-5, itmeans that A is a carbon and forms a ring with itself with 2-5 CH₂groups, which could also be represented structurally as

The variable “A” is not limited to carbon and can be another atom, suchas, but not limited to, a heteroatom, but the context in which thevariable is used will indicate the type of atom “A” could be. This isjust a non-limiting example. Additionally, the ring that is formed with“A” can also be substituted. Exemplary substituents are describedherein.

In some embodiments, heterocycles include, but are not limited to,pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl,and thiazolidinyl, all of which may be optionally substituted.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-memberedmonocyclic or bicyclic aromatic ring which consists of carbon atoms andone or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur.In the case of bicyclic heterocyclic aromatic rings, only one of the tworings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be(e.g., quinoline). The second ring can also be fused or bridged asdefined above for heterocycles. The nitrogen atom can be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The nitrogen and sulfur heteroatoms can optionally be oxidized(i.e., N→O and S(O_(p), wherein p=1 or 2). In certain compounds, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio,means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkythio group,respectively, substituted one or more times independently with asubstituent selected from the group consisting of halo, hydroxy, andC₁-C₃ alkoxy. By way of illustration, but without limitation, examplesinclude trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl,3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio,3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. In someembodiments, substitutions include substitution 1-5 times with halo,each independently selected, or substituted 1-3 times with halo and 1-2times independently with a group selected from hydroxy and C₁-C₃ alkoxy,or substituted 1-3 times independently with a group selected fromhydroxy and C₁-C₃ alkoxy, provided that no more than one hydroxy and/oralkoxy substituent may be attached through the same carbon.

The terms “substituted phenyl” and “substituted heterocycle” are takento mean that the cyclic moiety in either case is substituted. They canbe substituted independently with one or more substituents. They can besubstituted independently with 1, 2, 3, 4, 5, 1-3, 1-4, or 1-5substituents. The substitution can be, independently, halo, alkyl, suchas, but not limited to, C₁-C₄ alkyl, alkoxy, such as but not limited to,C₁-C₄ alkoxy, and alklylthio, such as but not limited to, C₁-C₄alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can befurther substituted independently with C₁-C₂ alkoxy or with one to fivehalo groups; or substituted with one substituent selected from the groupconsisting of phenyloxy, benzyloxy, phenylthio, benzylthio, andpyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio,benzylthio, and pyrimidinyloxy moiety can be further substituted withone to two substituents selected from the group consisting of halo,C₁-C₂ alkyl, and C₁-C₂ alkoxy; or substituted with one substituentselected from the group consisting of C₁-C₄ acyl and C₁-C₄alkoxycarbonyl, and further substituted with zero to one substituentselected from the group consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,and C₁-C₄ alkylthio. When a substituent is halo, in some embodiments,the halo groups are fluoro, chloro, and bromo. The halo can also beiodo.

DMF means N,N-dimethylformamide.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipients and salt must be compatible with the activeingredient of the formulation (e.g. a compound described herein). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic. The present disclosure includes pharmaceutically acceptablesalts of any compound(s) described herein. In some embodiments, thepharmaceutically acceptable salt is a hydrochloric salt.

Pharmaceutically acceptable salts can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting the free acidor base forms of these compounds with a stoichiometric amount of theappropriate base or acid in water or in an organic solvent, or in amixture of the two; generally, non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile, and the like. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 18thed., Mack Publishing Company, Easton, Pa., USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds described herein can be delivered in prodrug form and canbe administered in this form for the treatment of disease. “Prodrugs”are intended to include any covalently bonded carriers that release anactive parent drug of described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs are prepared by modifyingfunctional groups present in the compound in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound. Prodrugs include compounds described herein whereina hydroxy, amino, or sulfhydryl group is bonded to any group that, whenthe prodrug is administered to a mammalian subject, it cleaves to form afree hydroxyl, free amino, or free sulfhydryl group, respectively.Examples of prodrugs include, but are not limited to, acetate, formate,and benzoate derivatives of alcohol and amine functional groups in thecompounds described herein.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” includes any effect e.g.,lessening, reducing, modulating, or eliminating, that results in theimprovement of the condition, disease, disorder, etc. “Treating” or“treatment” of a disease state means the treatment of a disease-state ina mammal, particularly in a human, and include: (a) inhibiting anexisting disease-state, i.e., arresting its development or its clinicalsymptoms; and/or (c) relieving the disease-state, i.e., causingregression of the disease state.

As used herein, “preventing” means causing the clinical symptoms of thedisease state not to develop i.e., inhibiting the onset of disease, in asubject that may be exposed to or predisposed to the disease state, butdoes not yet experience or display symptoms of the disease state.

As used herein, “mammal” refers to human and non-human patients.

As used herein, the term “therapeutically effective amount” refers to acompound, or a combination of compounds, described herein present in oron a recipient in an amount sufficient to elicit biological activity,e.g. pain relief. In some embodiments, the combination of compounds is asynergistic combination. Synergy, as described, for example, by Chou andTalalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when theeffect of the compounds when administered in combination is greater thanthe additive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased decrease in pain, or some other beneficialeffect of the combination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions described herein also consistessentially of, or consist of, the recited components, and that theprocesses described herein also consist essentially of, or consist of,the recited processing steps. Further, it should be understood that theorder of steps or order for performing certain actions are immaterial solong as the process remains operable. Moreover, two or more steps oractions can be conducted simultaneously.

All enantiomers, diastereomers, and mixtures thereof, are includedwithin the scope of compounds described herein. In some embodiments, acomposition comprising the R enantiomer is free or substantially free ofthe S enantiomer. In some embodiments, a composition comprising the Senantiomer is free or substantially free of the R enantiomer. In someembodiments, a composition comprises an enantiomeric excess of at least,or about, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of either theR or the S enantiomer.

As used throughout this disclosure, the singular forms “a,” “an,” and“the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, a reference to “a composition” includes aplurality of such compositions, as well as a single composition, and areference to “a therapeutic agent” is a reference to one or moretherapeutic and/or pharmaceutical agents and equivalents thereof knownto those skilled in the art, and so forth. Thus, for example, areference to “a host cell” includes a plurality of such host cells, anda reference to “an antibody” is a reference to one or more antibodiesand equivalents thereof known to those skilled in the art, and so forth.

The compounds described herein and used in various embodiments describedherein can be prepared according to any method, and for example, asdescribed in U.S. Pat. No. 8,835,488, which is hereby incorporated byreference in its entirety.

The following compounds, or pharmaceutically acceptable salts thereof,can be used in any of the methods and embodiments described herein.These compounds are also described, for example, in U.S. Pat. No.8,835,488, which is hereby incorporated by reference in its entirety.

Compound. Name 1 2-[9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethan-1-amine 2 2-[(9R)-9-(pyridin-2-yl)- 6-oxaspiro[4.5]decan- 9-yl]ethan-1-amine 3 2-[9-(2-aminoethyl)-6- oxaspiro[4.5]decan-9-yl]pyridin-4-ol 4 6-[9-(2-aminoethyl)-6- oxaspiro[4.5]decan-9-yl]pyridin-3-ol 5 6-[9-(2-aminoethyl)-6- oxaspiro[4.5]decan-9-yl]pyridin-2-ol 6 2-[(9R)-9-(2- aminoethyl)-6- oxaspiro[4.5]decan-9-yl]-1-oxidopyridin-1- ium 7 benzyl({2-[1-(4-fluorophenyl)cyclohexyl]ethyl})amine 8 benzyl({2-[4-(4-fluorophenyl)oxan-4- yl]ethyl})amine 9 [(2- methylphenyl)methyl]({2-[4-(4- methylphenyl)oxan-4- yl]ethyl})amine 10 N-{2-[2,2-dimethyl-4-(4-methylphenyl)oxan- 4- yl]ethyl}aniline 11 2-[({2-[4-(4-methylphenyl)oxan-4- yl]ethyl}amino)methyl]phenol 12 2-[({2-[4-(4-fluorophenyl)oxan-4- yl]ethyl}amino)methyl]phenol 13benzyl({2-[3-(pyridin-2- yl)-1- oxaspiro[4.4]nonan-3- yl]ethyl})amine 14benzyl({2-[2,2- dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl})amine 15{2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}(pyridin-2-ylmethyl)amine 16 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}(pyridin-3- ylmethyl)amine 17 [(2- methoxyphenyl)methyl]({2-[4-(4- methylphenyl)oxan-4- yl]ethyl})amine 18 (furan-3-ylmethyl)({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 19(1H-imidazol-2- ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 20 (1,3-oxazol-4-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 21 {2-[3-(pyridin-2-yl)-1- oxaspiro[4.4]nonan-3-yl]ethyl}(thiophen-2- ylmethyl)amine 22 {2-[3-(pyridin-2-yl)-1-oxaspiro[4.4]nonan-3- yl]ethyl}(thiophen-3- ylmethyl)amine 23(cyclopentylmethyl)({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 24 {2-[2,2-dimethyl-4- (4-methylphenyl)oxan-4-yl]ethyl}(thiophen-2- ylmethyl)amine 25 {2-[4-(4- fluorophenyl)oxan-4-yl]ethyl}[(2- methoxyphenyl)methyl]amine 26 {2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl}(thiophen-2- ylmethyl)amine 27benzyl({2-[(9S)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 28 benzyl({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 29 benzyl({2-[3-(pyridin-2- yl)-1-oxaspiro[4.5]decan-3- yl]ethyl})amine 30 benzyl({2-[9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 31 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}[(2- methylphenyl)methyl]amine 32{2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}[(3-methylphenyl)methyl]amine 33 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}[(4- methylphenyl)methyl]amine 34 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}[(1R)-1- phenylethyl]amine 35{2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}[(1S)-1-phenylethyl]amine 36 benzyl({2-[2,2- dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl})methylamine 37 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}(2- phenylethyl)amine 38 (pyrazin-2- ylmethyl)({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 39benzyl({2-[2,2-diethyl- 4-(pyridin-2-yl)oxan-4- yl]ethyl})amine 40benzyl({2-[2,2,6,6- tetramethyl-4-(pyridin- 2- yl)oxan-4-yl]ethyl})amine 41 4-[({2-[2,2-dimethyl-4- (4-methylphenyl)oxan- 4-yl]ethyl}amino)methyl]phenol 42 2-[({2-[2,2-dimethyl-4-(4-methylphenyl)oxan- 4- yl]ethyl}amino)methyl]phenol 433-[({2-[2,2-dimethyl-4- (4-methylphenyl)oxan- 4-yl]ethyl}amino)methyl]phenol 44 [(5-methylfuran-2-yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 45 [(5-methylfuran-2- yl)methyl]({2-[9-(pyrazin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 46benzyl({2-[9-(thiophen- 2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine47 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}[(2-fluorophenyl)methyl]amine 48 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}[(3- fluorophenyl)methyl]amine 49 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}[(4- fluorophenyl)methyl]amine 50benzyl(2-{9-cyclohexyl- 6-oxaspiro[4.5]decan- 9- yl}ethyl)amine 51{2-[3-(pyridin-2-yl)-1- oxaspiro[4.5]decan-3- yl]ethyl}(thiophen-2-ylmethyl)amine 52 {2-[3-(pyridin-2-yl)-1- oxaspiro[4.5]decan-3-yl]ethyl}(thiophen-3- ylmethyl)amine 53 {2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2- ylmethyl)amine 54{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2- ylmethyl)amine 55 {2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3- ylmethyl)amine 56{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(1,3-thiazol-2- ylmethyl)amine 57 {2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(1,3-thiazol-5- ylmethyl)amine 58{2-[9-(pyrazin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2-ylmethyl)amine 59 {2-[2,2-diethyl-4- (pyridin-2-yl)oxan-4-yl]ethyl}(thiophen-3- ylmethyl)amine 60 {2-[2,2-diethyl-4-(pyridin-2-yl)oxan-4- yl]ethyl}(thiophen-2- ylmethyl)amine 61{2-[2,2,6,6- tetramethyl-4-(pyridin- 2-yl)oxan-4- yl]ethyl}(thiophen-2-ylmethyl)amine 62 {2-[2,2,6,6- tetramethyl-4-(pyridin- 2-yl)oxan-4-yl]ethyl}(thiophen-3- ylmethyl)amine 63 {2-[9-(thiophen-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2- ylmethyl)amine 64{2-[9-(thiophen-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3-ylmethyl)amine 65 (cyclopentylmethyl)({2- [2,2-diethyl-4-(4-fluorophenyl)oxan-4- yl]ethyl})amine 66 (cyclopentylmethyl)({2-[4-(4-fluorophenyl)- 2,2,6,6- tetramethyloxan-4- yl]ethyl})amine 67(2-{9-cyclohexyl-6- oxaspiro[4.5]decan-9- yl}ethyl)(thiophen-2-ylmethyl)amine 68 (2-{9-cyclohexyl-6- oxaspiro[4.5]decan-9-yl}ethyl)(thiophen-3- ylmethyl)amine 69 2-{2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}-2,3-dihydro- 1H-isoindole 70{2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4- yl]ethyl}dipropylamine 71(2-phenylethyl)({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 72 (2-phenylethyl)({2-[9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 73 benzyl({2-[9-(6-methylpyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 74{2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}(2- phenylpropan-2-yl)amine 75 {2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3- yl)ethyl]amine 76 [(2-methylpyrimidin-5-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 77 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}[(2- methoxyphenyl)methyl]amine 78 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}[(3- methoxyphenyl)methyl]amine 79benzyl({2-[9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine80 benzyl({2-[(9S)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 81 benzyl({2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 82 2-[(9R)-9-(2-{4H,5H,6H-thieno[2,3- c]pyrrol-5- yl}ethyl)-6- oxaspiro[4.5]decan-9-yl]pyridine 83 [(4,5-dimethylfuran-2- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 84{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-4- ylmethyl)amine 85 2-[({2-[4-(4- methoxyphenyl)-2,2-dimethyloxan-4- yl]ethyl}amino)methyl]phenol 86 benzyl({2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4- yl]ethyl})amine 87 benzyl({2-[4-(4-fluorophenyl)-2,2,6,6- tetramethyloxan-4- yl]ethyl})amine 88 [(2,3-dimethoxyphenyl)methyl]({2- [4-(4- methylphenyl)oxan-4- yl]ethyl})amine89 [(3-methylthiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 90 {2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[2-(thiophen- 2-yl)ethyl]amine 91[(2-methylthiophen-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 92 [(5-methylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 93 {2-[9-(6-methylpyridin- 2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3- ylmethyl)amine 94{2-[4-(4-fluorophenyl)- 1- oxaspiro[5.5]undecan- 4-yl]ethyl}(1H-pyrrol-2- ylmethyl)amine 95 {2-[9-(6-methylpyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2- ylmethyl)amine 96[(4-methylthiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 97 {2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[(5- methylfuran-2- yl)methyl]amine 98[(4-methyl-1,3-thiazol- 2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 99 [(2-methyl-1,3-thiazol-5-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 100 [(4-methyl-1,3-thiazol- 5-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 101 [(2-chlorophenyl)methyl]({2- [2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl})amine 102 [(3- chlorophenyl)methyl]({2- [2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl})amine 103 [(4- chlorophenyl)methyl]({2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl})amine 1046-[9-{2-[(thiophen-2- ylmethyl)amino]ethyl}- 6- oxaspiro[4.5]decan-9-yl]pyridin-3-ol 105 6-[9-{2-[(thiophen-2- ylmethyl)amino]ethyl}-6-oxaspiro[4.5]decan- 9-yl]pyridin-2-ol 106 [(5-methylthiophen-2-yl)methyl]({2-[2,2,6,6- tetramethyl-4-(pyridin- 2-yl)oxan-4-yl]ethyl})amine 107 2-(9-{2-[(thiophen-2- ylmethyl)amino]ethyl}- 6-oxaspiro[4.5]decan-9- yl)pyridin-4-ol 108 [(4-methylthiophen-2-yl)methyl]({2-[2,2,6,6- tetramethyl-4-(pyridin- 2-yl)oxan-4-yl]ethyl})amine 109 dibutyl({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 110 {2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3-ylmethyl)amine 111 {2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2- ylmethyl)amine 112 (cyclopentylmethyl)({2-[4-(4-fluorophenyl)-1- oxaspiro[5.5]undecan- 4-yl]ethyl})amine 113{2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4- yl]ethyl}(thiophen-3-ylmethyl)amine 114 {2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4-yl]ethyl}(thiophen-2- ylmethyl)amine 115 {2-[4-(4-fluorophenyl)-2,2,6,6- tetramethyloxan-4- yl]ethyl}(thiophen-3- ylmethyl)amine 116{2-[4-(4-fluorophenyl)- 2,2,6,6- tetramethyloxan-4-yl]ethyl}(thiophen-2- ylmethyl)amine 117 benzyl({2-[9-(2-methoxyphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 118benzyl({2-[9-(6- methoxypyridin-2-yl)- 6- oxaspiro[4.5]decan-9-yl]ethyl})amine 119 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}[(2- methoxyphenyl)methyl]methylamine 120{2-[9-(4-fluorophenyl)- 6-oxaspiro[4.5]decan- 9- yl]ethyl}[(3-methylphenyl)methyl]amine 121 {2-[(9S)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[(3- methylphenyl)methyl]amine 122{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylphenyl)methyl]amine 123 benzyl({2-[4-(4- fluorophenyl)-1-oxaspiro[5.5]undecan- 4-yl]ethyl})amine 124 {2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(1R)-1-phenylethyl]amine 125 {2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[(1S)-1- phenylethyl]amine 126{2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4- yl]ethyl}[(2-nitrophenyl)methyl]amine 127 {2-[2,2-dimethyl-4-(4- methylphenyl)oxan-4-yl]ethyl}[(3- nitrophenyl)methyl]amine 128 2-[({2-[9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]phenol 129{2-[4-(4- methoxyphenyl)-2,2- dimethyloxan-4- yl]ethyl}[(2-methoxyphenyl)methyl]amine 130 [(5-ethylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 131 [(3,5- dimethylthiophen-2- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 132{2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4- yl]ethyl}[(6-methylpyridin-3- yl)methyl]amine 133 {2-[4-(4-fluorophenyl)- 2,2,6,6-tetramethyloxan-4- yl]ethyl}[(6- methylpyridin-3- yl)methyl]amine 134[(4,5- dimethylthiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 135 [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]({2- [(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 136 {2-[9-(pyrazin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2- ylmethyl)amine 137[(4,5-dimethylfuran-2- yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 138 {2-[9-(2- methoxyphenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-2- ylmethyl)amine 139 {2-[9-(2-methoxyphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3-ylmethyl)amine 140 [(3-methoxythiophen- 2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 141[(3-methoxythiophen- 2-yl)methyl]({2-[9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 142 {2-[9-(6-methoxypyridin-2-yl)- 6-oxaspiro[4.5]decan- 9- yl]ethyl}(thiophen-2-ylmethyl)amine 143 {2-[9-(6- methoxypyridin-2-yl)- 6-oxaspiro[4.5]decan-9- yl]ethyl}(thiophen-3- ylmethyl)amine 144 {2-[4-(4-chlorophenyl)-2,2-dimethyloxan-4- yl]ethyl}[(2- methoxyphenyl)methyl]amine 145{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(5-methylthiophen-2- yl)methyl]amine 146 {2-[4-(4-fluorophenyl)- 1-oxaspiro[5.5]undecan- 4- yl]ethyl}(thiophen-3- ylmethyl)amine 147{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylthiophen-2- yl)methyl]amine 148 {2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[(4- methylthiophen-2- yl)methyl]amine149 {2-[4-(4-fluorophenyl)- 1- oxaspiro[5.5]undecan- 4-yl]ethyl}(thiophen-2- ylmethyl)amine 150 {2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}[(4-methyl-1,3- thiazol-2-yl)methyl]amine 151 {2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4-yl]ethyl}[(5- methylthiophen-2- yl)methyl]amine 152[(5-chlorothiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 153 dibutyl({2-[4-(4-fluorophenyl)-2,2,6,6- tetramethyloxan-4- yl]ethyl})amine 154{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}(2-phenylpropan-2- yl)amine 155 {4H,5H,6H- cyclopenta[b]thiophen-2-ylmethyl}({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 156 {2-[4-(4-fluorophenyl)- 1- oxaspiro[5.5]undecan- 4-yl]ethyl}[(6- methylpyridin-3- yl)methyl]amine 157 [(2,3-dimethoxyphenyl)methyl]({2- [2,2-dimethyl- 4- (4-methylphenyl)oxan-4-yl]ethyl})amine 158 [(2,4- dimethoxyphenyl)methyl]({2- [2,2-dimethyl-4- (4-methylphenyl)oxan- 4-yl]ethyl})amine 159 {2-[9-(4-fluorophenyl)-6-oxaspiro[4.5]decan- 9-yl]ethyl}[(4- methoxyphenyl)methyl]amine 160[(5-propylthiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 161 1-{5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]thiophen-2-yl}ethan-1- ol 162 6-[9-(2-{[(4,5- dimethylthiophen-2-yl)methyl]amino}ethyl)- 6-oxaspiro[4.5]decan- 9- yl]pyridin-3-ol 1636-[9-(2-{[(4,5- dimethylthiophen-2- yl)methyl]amino}ethyl)-6-oxaspiro[4.5]decan- 9- yl]pyridin-2-ol 164 2-[9-(2-{[(4,5-dimethylthiophen-2- yl)methyl]amino}ethyl)- 6-oxaspiro[4.5]decan- 9-yl]pyridin-4-ol 165 [(5-nitrothiophen-2- yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 166 [(3,5-dimethylthiophen-2- yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 167 [(5-ethylthiophen-2-yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 168 {2-[4-(4-fluorophenyl)- 1- oxaspiro[5.5]undecan-4-yl]ethyl}[(5- methylthiophen-2- yl)methyl]amine 169 [(4,5-dimethylthiophen-2- yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 170 {[5- (methylsulfanyl)thiophen-2-yl]methyl}({2- [(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 171 6-[9-(2-{[(3- methoxythiophen-2-yl)methyl]amino}ethyl)- 6-oxaspiro[4.5]decan- 9- yl]pyridin-3-ol 1726-[9-(2-{[(3- methoxythiophen-2- yl)methyl]amino}ethyl)-6-oxaspiro[4.5]decan- 9- yl]pyridin-2-ol 173 2-[(9R)-9-(2-{[(3-methoxythiophen-2- yl)methyl]amino}ethyl)- 6-oxaspiro[4.5]decan-9-yl]-1- oxidopyridin-1-ium 174 2-[9-(2-{[(3- methoxythiophen-2-yl)methyl]amino}ethyl)- 6-oxaspiro[4.5]decan- 9- yl]pyridin-4-ol 175{2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methoxythiophen-2- yl)methyl]amine 176 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}({[3-(trifluoromethyl)phenyl]methyl})amine 177 (1-benzothiophen-2-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 178 (1-benzothiophen-3- ylmethyl)({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 179[(5-chlorothiophen-2- yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 180 2-{[(2-{2,2-dimethyl-4- [4-(trifluoromethyl)phenyl]oxan- 4- yl}ethyl)amino]methyl}phenol 181[(5-chlorothiophen-2- yl)methyl]({2-[2,2- diethyl-4-(4-fluorophenyl)oxan- 4-yl]ethyl})amine 182 {[5-(2-methylpropyl)thiophen- 2-yl]methyl}({2-[(9R)- 9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 183 [(5-butylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 184 {4H,5H,6H- cyclopenta[b]thiophen- 2-ylmethyl}({2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 185{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2H,3H-thieno[3,4- b][1,4]dioxin-5- ylmethyl})amine 186 {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4- yl]ethyl}[(2- methanesulfonylphenyl)methyl]amine187 [(4-bromofuran-2- yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 188 {2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[5-(methylsulfanyl)thiophen- 2- yl]methyl})amine 189 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[6- (trifluoromethyl)pyridin- 3-yl]methyl})amine 190 [(5-bromofuran-2- yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 191(2-{2,2-dimethyl-4-[4- (trifluoromethyl)phenyl]oxan- 4- yl}ethyl)[(2-methoxyphenyl)methyl]amine 192 {2-[2,2,6,6- tetramethyl-4-(pyridin-2-yl)oxan-4- yl]ethyl}({[6- (trifluoromethyl)pyridin- 3-yl]methyl})amine 193 {[5-(furan-2- yl)thiophen-2- yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 194[(5-chlorothiophen-2- yl)methyl]({2-[4-(4- fluorophenyl)-1-oxaspiro[5.5]undecan- 4- yl]ethyl})amine 195 (1-benzothiophen-2-ylmethyl)({2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 196 (1-benzothiophen-3- ylmethyl)({2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 197 [(5-fluoro-1-benzothiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 198 [(5- cyclopentylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 199 [(4- phenylphenyl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 200 [(3-phenylphenyl)methyl]({2- [(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 201 benzyl({2-[9-(4-bromophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 2022-amino-4-chloro-5- [({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]thiophene- 3- carbonitrile203 {2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({2H,3H- thieno[3,4- b][1,4]dioxin-5- ylmethyl})amine 204[(4-phenylthiophen-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 205 [(5-phenylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 206 [(5- methanesulfonylthiophen- 2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 207[(4-bromothiophen-3- yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 208 [(4-bromothiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 209 [(5-bromothiophen-2- yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 210[(2-bromothiophen-3- yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 211 [(5-bromofuran-2-yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 212 {2-[(9R)-9-(4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}({[6- (trifluoromethyl)pyridin- 3-yl]methyl})amine 213 [(4-bromofuran-2- yl)methyl]({2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 214{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(thiophen- 2-yl)thiophen-2- yl]methyl})amine 215{2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4- yl]ethyl}({[6-(trifluoromethyl)pyridin- 3- yl]methyl})amine 216 [(5-chloro-1-benzothiophen-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 217 [(5-bromo-4- methylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 218 [(4-bromo-5- methylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 219 [(3-bromo-5- methylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 220 [(4-bromo-3- methylthiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 221 {2-[4-(4-fluorophenyl)- 1- oxaspiro[5.5]undecan- 4-yl]ethyl}({[6- (trifluoromethyl)pyridin- 3- yl]methyl})amine 222[(4-bromothiophen-3- yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 223 [(4-bromothiophen-2-yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 224 [(5-bromothiophen-2- yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 225dibenzyl({2-[(9R)-9-(4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 226 dibenzyl({2-[2,2- diethyl-4-(4- fluorophenyl)oxan-4-yl]ethyl})amine 227 [(4-bromo-3- methylthiophen-2-yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 228 [(4-bromo-5- methylthiophen-2-yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 229 [(3-bromo-5- methylthiophen-2-yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 230 [(5-bromo-4- methylthiophen-2-yl)methyl]({2-[(9R)-9- (4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 231 {2-[2,2-diethyl-4-(4- fluorophenyl)oxan-4-yl]ethyl}bis(thiophen- 2-ylmethyl)amine 232 [(4,5- dibromothiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 233 [(3,4- dibromothiophen-2- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 234 [(4,5-dibromothiophen-2- yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 235 [(3,4- dibromothiophen-2-yl)methyl]({2-[(9R)-9- (4- fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 236 [(2- fluorophenyl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 237 [(2-bromophenyl)methyl]({2- [(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 238 [(2- chlorophenyl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 239 [(2-methylphenyl)methyl]({2- [(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 240 {2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[2- (trifluoromethyl)phenyl]methyl})amine 2412-[({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]phenol 242 [(2- methoxyphenyl)methyl]({2- [(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 243 [(3-fluorophenyl)methyl]({2- [(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 244 [(3- bromophenyl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 245 [(3-chlorophenyl)methyl]({2- [(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 246 [(3- methylphenyl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 247 methyl3-[({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]benzoate 248 3-[({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl}amino)methyl]phenol 249{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan- 9- yl]ethyl}({[3-(trifluoromethyl)phenyl]methyl})amine 250 N-methyl-5-[({2-[(9R)-9-(pyridin-2-yl)- 6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]thiophene- 2- carboxamide 251N-ethyl-5-[({2-[(9R)- 9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]thiophene- 2- carboxamide 252 N-methyl-3-[({2-[(9R)-9-(pyridin-2-yl)- 6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]benzamide 253 N-ethyl-3-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]benzamide 254 [(4- methoxyphenyl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 2554-[({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]phenol 256 [(2,3- difluorophenyl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 257[(2,4- difluorophenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 258 [(2,5-difluorophenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 259 [(2,6-difluorophenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 260 [(3,4-difluorophenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 261 [(3,5-difluorophenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 262 [(2,3-dimethoxyphenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 263 [(3,4-dimethoxyphenyl)methyl]({2- [(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 264 2-methoxy-4-[({2-[(9R)-9-(pyridin-2-yl)- 6- oxaspiro[4.5]decan- 9-yl]ethyl}amino)methyl]phenol 265 [(5-fluoropyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 266 [(5-bromopyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 267[(5-chloropyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 268 [(5-methoxypyridin-3-yl)methyl]({2-[(9R)- 9- (pyridin-2-yl)-6- oxaspiro[4.5]decan- 9-yl]ethyl})amine 269 5-[({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl}amino)methyl]pyridine- 3-carbonitrile270 [(5-methylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2- yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl})amine 271 {2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl}({[5- (trifluoromethyl)pyridin- 3-yl]methyl})amine 272 {[6-chloro-5- (trifluoromethyl)pyridin- 3-yl]methyl}({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 273 {[2-fluoro-5- (trifluoromethyl)pyridin- 3-yl]methyl}({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 274 {[6-fluoro-5- (trifluoromethyl)pyridin- 3-yl]methyl}({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 275 {2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({[3- (trifluoromethyl)pyridin- 2- yl]methyl})amine 276{2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan- 9- yl]ethyl}({[4-(trifluoromethyl)pyridin- 3- yl]methyl})amine 277 {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan- 9- yl]ethyl}({[4- (trifluoromethyl)pyridin-2- yl]methyl})amine 500 [(4- chlorophenyl)methyl]({2- [4-(4-methoxyphenyl)- 2,2-dimethyloxan-4- yl]ethyl})amine 501 [(3,4-dimethoxyphenyl)methyl][2- (2,2-dimethyl-4- phenyloxan-4- yl)ethyl]amine502 2-[({2-[2-ethyl-2- methyl-4-(4- methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol 503 [2-(2,2-dimethyl-4- phenyloxan-4-yl)ethyl][(2- fluorophenyl)methyl]amine 504 4-[({2-[4-(2-methoxyphenyl)-2,2- dimethyloxan-4- yl]ethyl}amino)methyl]-N,N-dimethylaniline 505 2-[({2-[2-ethyl-4-(4- fluorophenyl)-2-methyloxan-4- yl]ethyl}amino)methyl]phenol 506.{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyrimidin-5- ylmethyl)amine 507. [(2-methylpyrimidin-5-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 508. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[2- (trifluoromethyl)pyrimidin-5- yl]methyl})amine 509.[(2-methoxypyrimidin-5- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 510.(pyridazin-4-ylmethyl)({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 511. [(6-methylpyridazin-4-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 512. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[6- (trifluoromethyl)pyridazin-4- yl]methyl})amine 513.[(6-methoxypyridazin-4- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 514.(pyrazin-2-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 515. [(6-methylpyrazin-2-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 516. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[6- (trifluoromethyl)pyrazin-2- yl]methyl})amine 517.[(6-methoxypyrazin-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 518. [(5-methylpyrazin-2-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 519. {2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyrazin-2- yl]methyl})amine 520.[(5-methoxypyrazin-2- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 521. {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(quinolin-3- ylmethyl)amine 522.(1H-pyrazol-3-ylmethyl)({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 523. [(1-methyl-1H-pyrazol-3-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 524. [(5-methyl-1H-pyrazol-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 525.[(1,5-dimethyl-1H-pyrazol-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 526.(1H-pyrazol-4-ylmethyl)({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 527. [(1-methyl-1H-pyrazol-4-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 528. [(5-methyl-1H-pyrazol-4-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 529. [(1,5-dimethyl-1H-pyrazol-4- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 530.[(5,6-difluoropyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 531. [(5-chloro-6-fluoropyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 532. [(5-bromo-6-fluoropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 533.[(6-fluoro-5-iodopyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 534.[(6-fluoro-5-methylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 535.[(6-fluoro-5-methoxypyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 536.2-fluoro-5-[({2-[(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 3-carbonitrile 537.[(6-chloro-5-fluoropyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 538. [(5,6-dichloropyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 539. [(5-bromo-6-chloropyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 540.[(6-chloro-5-iodopyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 541. [(6-chloro-5-methylpyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 542. [(6-chloro-5-methoxypyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 543. 2-chloro-5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]pyridine-3-carbonitrile 544. 3-fluoro-5-[({2-[(9R)-9-(pyridin- 2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]pyridine- 2-carbonitrile545. 3-chloro-5-[({2-[(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2-carbonitrile 546.3-bromo-5-[({2-[(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2-carbonitrile 547.3-iodo-5-[({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2-carbonitrile 548.3-methyl-5-[({2-[(9R)-9-(pyridin- 2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2-carbonitrile 549.3-methyl-5-[({2-[(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2-carbonitrile 550.5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 2,3-dicarbonitrile 551.5-[({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]-3- (trifluoromethyl)pyridine-2- carbonitrile 552.{[5-fluoro-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 553. {[5-chloro-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 554. {[5-bromo-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 555. {[5-iodo-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 556. {[5-methyl-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 557. {[5-methoxy-6- (trifluoromethyl)pyridin-3-yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 558. 5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]-2-(trifluoromethyl)pyridine-3- carbonitrile 559.{[5,6-bis(trifluoromethyl)pyridin- 3-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 560.[(5-fluoro-6-methylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 561. [(5-chloro-6-methylpyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 562. [(5-bromo-6-methylpyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 563.[(5-iodo-6-methylpyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 564.[(5,6-dimethylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 565.[(5-methoxy-6-methylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 566.2-methyl-5-[({2-[(9R)-9-(pyridin- 2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 3-carbonitrile 567. {[6-methyl-5-(trifluoromethyl)pyridin-3- yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 568.[(5-fluoro-6-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 569.[(5-chloro-6-methoxypyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 570. [(5-bromo-6-methoxypyridin-3-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 571. [(5-iodo-6-methoxypyridin-3- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- l]ethyl})amine 572.[(6-methoxy-5-methylpyridin-3- yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 573. [(5,6-dimethoxypyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 574. 2-methoxy-5-[({2-[(9R)-9-(pyridin- 2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}amino)methyl]pyridine-3- carbonitrile575. 2-methoxy-5-[({2-[(9R)-9- (pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]pyridine- 3-carbonitrile 576. {[6-methoxy-5-(trifluoromethyl)pyridin-3- yl]methyl}({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 576[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-phenyl-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 577 {2-[(9R)-9-phenyl-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3-yl]methyl})amine 578 {2-[(9R)-9-phenyl-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4-(trifluoromethyl)pyridin- 3- yl]methyl})amine 579[(3,5-difluorophenyl)methyl]({2- [(9R)-9-phenyl-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 580 [(3-methylphenyl)methyl]({2-[(9R)-9- phenyl-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 581[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine 582{2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyridin-3- yl]methyl})amin 583{2-[(9R)-9-(4-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4-(trifluoromethyl)pyridin- 3- yl]methyl})amine 584[(3,5-difluorophenyl)methyl]({2- [(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine 585[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-[4-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 586{2-[(9R)-9-[4- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3-yl]methyl})amine 587 {2-[(9R)-9-[4- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3-yl]methyl})amine 588 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[4-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 589[(3-methylphenyl)methyl]({2-[(9R)-9- [4- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 590[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 591{2-[(9R)-9-(pyridin-3-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyridin- 3- yl]methyl})amine 592{2-[(9R)-9-(pyridin-3-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine 593[(3,5-difluorophenyl)methyl]({2- [(9R)-9-(pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 594[(3-methylphenyl)methyl]({2-[(9R)-9- (pyridin-3-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 595[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 596{2-[(9R)-9-(pyridin-4-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyridin- 3- yl]methyl})amine 597{2-[(9R)-9-(pyridin-4-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine 598[(3,5-difluorophenyl)methyl]({2- [(9R)-9-(pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 599[(3-methylphenyl)methyl]({2-[(9R)-9- (pyridin-4-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 600[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-(3- methylphenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 601 {2-[(9R)-9-(3-methylphenyl)-6-oxaspiro[4.5]decan-9- yl]ethyl}({[5-(trifluoromethyl)pyridin- 3-yl]methyl})amine 602 {2-[(9R)-9-(3-methylphenyl)-6-oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3-yl]methyl})amine 603 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-(3-methylphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 604{2-[(9R)-9-(3-methylphenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylphenyl)methyl]amine 605 [(5-chloropyridin-3-yl)methyl]({2-[(9R)-9-[3- (trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 606 {2-[(9R)-9-[3- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3-yl]methyl})amine 607 {2-[(9R)-9-[3- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3-yl]methyl})amine 608 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[3-(trifluoromethoxy)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 609[(3-methylphenyl)methyl]({2-[(9R)-9- [3- (trifluoromethoxy)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 610[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-[4-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 611{2-[(9R)-9-[4- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3-yl]methyl})amine 612 {2-[(9R)-9-[4- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3-yl]methyl})amine 613 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[4-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 614[(3-methylphenyl)methyl]({2-[(9R)-9- [4- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 615[(5-chloropyridin-3-yl)methyl]({2- [(9R)-9-(3-fluorophenyl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine 616{2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyridin- 3- yl]methyl})amine 617{2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[4-(trifluoromethyl)pyridin-3- yl]methyl})amine 618[(3,5-difluorophenyl)methyl]({2- [(9R)-9-(3-fluorophenyl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine 619{2-[(9R)-9-(3-fluorophenyl)-6- oxaspiro[4.5]decan-9- yl]ethyl}[(3-methylphenyl)methyl]amine 620 [(5-chloropyridin-3-yl)methyl]({2-[(9R)-9-[3- (trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 621 {2-[(9R)-9-[3- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5- (trifluoromethyl)pyridin-3-yl]methyl})amine 622 {2-[(9R)-9-[3- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9-yl]ethyl}({[4- (trifluoromethyl)pyridin-3-yl]methyl})amine 623 [(3,5-difluorophenyl)methyl]({2- [(9R)-9-[3-(trifluoromethyl)phenyl]-6- oxaspiro[4.5]decan-9- yl]ethyl})amine 624[(3-methylphenyl)methyl]({2-[(9R)-9- [3- (trifluoromethyl)phenyl]-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 625 [(5-chloropyridin-3-yl)methyl](methyl){2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan- 9-yl]ethyl}amine 626 methyl({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}){[5- (trifluoromethyl)pyridin-3-yl]methyl}amine 627 [(5-chloropyridin-3-yl)methyl-(2H2)]{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}amine 628({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}){[5-(trifluoromethyl)pyridin-3-yl]methyl- (2H2)}amine 629{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[6-(trifluoromethyl)pyridin-2- yl]methyl})amine 630{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[5-(trifluoromethyl)pyridin- 2-yl]methyl})amine 631{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-2-ylmethyl)amine 632 {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl}(pyridin-3-ylmethyl)amine 633{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}(pyridin-4-ylmethyl)amine 634(1H-imidazol-4-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 635[(2-methylpyridin-4-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 636{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl}({[2-(trifluoromethyl)pyridin- 4- yl]methyl})amine 637[(6-chloropyridin-3-yl)methyl]({2- [(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 638[(1-methyl-1H-imidazol-2- yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan- 9- yl]ethyl})amine 639(naphthalen-2-ylmethyl)({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 640 [(6-bromo-5-fluoropyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 641 [(5-methanesulfonylpyridin-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethyl})amine 642 [2-(3-methylphenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 643[2-(3-chlorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 644[2-(3-bromophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 645[2-(3-fluorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 646{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[3-(trifluoromethyl)phenyl]ethyl})amine 647[2-(3-methoxyphenyl)ethyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 648[2-(4-methylphenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 649[2-(4-chlorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 650[2-(4-bromophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 651[2-(4-fluorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 652{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[4-(trifluoromethyl)phenyl]ethyl})amine 653[2-(4-methoxyphenyl)ethyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 654[2-(2-methylphenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 655[2-(2-chlorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 656[2-(2-bromophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 657[2-(2-fluorophenyl)ethyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine 658{2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9- yl]ethyl}({2-[2-(trifluoromethyl)phenyl]ethyl})amine 659[2-(2-methoxyphenyl)ethyl]({2-[(9R)- 9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

EXAMPLES Example 1

Biased ligands do not induce hyperalgesia. Compounds were tested fortheir potential to induce hyperalgesia in a mouse model of opioidinduced hyperalgesia. In this test mice (n=8/group) are givensubcutaneous injections of vehicle or mu opioid agonists twice per dayfor four days. On each of the four drug treatment days a measurement ofmechanical allodynia was obtained using a method of repeated stimulationwith a single von Frey monofilament (0.4 g). On the fifth day animalsare again tested with no additional drug treatments. For testing, themonofilament is delivered to the hind paw for approximately 1-2 seconds.If there is a withdrawal response, that is recorded as a positiveresponse. This is repeated ten times for each mouse. The finalmeasurement for each mouse is the % non-response to stimulation for theten trials. The results are shown in FIG. 1. Compound A is Compound 265and Compound B is Compound 54.

The figures illustrate the percent of non-responses to 10 applicationsof a 0.4 g von Frey filament in mice treated with indicated mu-opioidagonists or vehicle over 4 days. Oxycodone and fentanyl decreased the %non-responses, an indication of increased sensitivity (hyperalgesia) tothe von Frey filament, while the biased mu-opioid agonists Compound Aand B, did not.

These results demonstrate that the biased ligands that target themu-opioid receptor do not induce hyperalgesia as compared to thenon-biased ligands that are fentanyl and oxycodone. These results weresurprising and unexpected. Therefore, based upon these results it isexpected that the compounds can be used to treat hyperalgesia orsubjects that have hyperalgesia or increased nociceptive sensitizationas described herein.

Example 2

Biased ligand reverse opioid induced hyperalgesia. In a mouse model ofopioid induced hyperalgesia, compounds were tested for their potentialto reverse opioid induced hyperalgesia. In this test mice (n=8/group)were given subcutaneous injections of vehicle or a reference mu opioidagonist twice per day for four days. On each of the four drug treatmentdays a measurement of mechanical allodynia was obtained using a methodof repeated stimulation with a single von Frey monofilament (0.4 g).After behavioral testing on the fifth day animals that had received areference mu opioid agonist were switched onto Compound B. Twice dailysubcutaneous injections continued through Day 12. A behavioralassessment of mechanical allodynia was made on days 5, 6, 7, 8, 10 and12. For testing, the monofilament is delivered to the hind paw forapproximately 1-2 seconds. If there was a withdrawal response, that wasrecorded as a positive response. This was repeated ten times for eachmouse. The final measurement for each mouse is the % non-response tostimulation for the ten trials. Compound B (Compound 54) was able toreverse of opioid induced hyperalgesic activity. Similar results wouldbe expected for Compound 140 and Compound 265 because they are alsobiased ligands like Compound 54. Accordingly, the results that wereproduced demonstrate that the biased ligands provided herein can reverseopioid induced hyperalgesic activity. Accordingly, the compoundsdescribed herein can be used to reverse opioid induced hyperalgesicactivity in humans or other mammals.

Example 3

A human subject who is prescribed morphine presents with symptoms ofopioid induced hyperalgesia. The subject stops being administered themorphine and is administered Compound 140 or Compound 265. The subject'sopioid induced hyperalgesia is treated and reduced. The subjectcontinues taking Compound 140 or Compound 265 and does not suffer fromhyperalgesia while maintaining the pain relief.

Example 4

A subject is identified as having increased nociceptive sensitizationdue to being administered an opioid for pain relief. The subject isswitched from the opioid to a pharmaceutical composition comprisingCompound 140 or Compound 265. The subject's nociceptive sensitization isdecreased while maintaining the pain relief.

The foregoing examples demonstrate that the compounds described hereindo not induce OIH in subjects being administered one or more of thecompounds described herein and can be used to treat pain in subjectswithout causing hyperalgesia or increased nociceptive sensitization. Theexamples also demonstrate that the biased ligans provided herein can beused to reverse opioid induced hyperalgesic activity in a mammal, suchas humans.

While the compounds and methods described herein have been describedwith reference to examples, those skilled in the art recognize thatvarious modifications may be made without departing from the spirit andscope thereof.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non-patent publications referred to in this specification and/orlisted in the Application Data Sheet are incorporated herein byreference, in their entirety.

What is claimed is:
 1. A method of reversing opioid induced hyperalgesiain a subject in need thereof comprising administering to the subject acompound having a formula of

or a pharmaceutically acceptable salt thereof, wherein R₂₃, and R₂₄ areeach independently null, H, OH, cycle, aryl, branched or unbranchedalkyl alcohol, halo, branched or unbranched alkyl, amine, amide, cyano,alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylsulfanyl; or R₂₃ and R₂₄together form an aryl or a cycle that is attached to one or more of theatoms of the thiophene ring.
 2. The method of claim 1, wherein thecompound has a formula of:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is a compound having a formula of

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 3,wherein R₂₃ is alkoxy.
 5. The method of claim 1, wherein R₂₄ is H. 6.The method of claim 1, wherein the compound, or a pharmaceuticallyacceptable salt thereof is administered in a pharmaceutical composition.7. The method of claim 1, wherein the compound has a formula of

or a pharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the compound has a formula of

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein the compound has a formula of

or a pharmaceutically acceptable salt thereof.
 10. The method of claim7, wherein the compound, or a pharmaceutically acceptable salt thereofis administered in a pharmaceutical composition.
 11. The method of claim8, wherein the compound, or a pharmaceutically acceptable salt thereofis administered in a pharmaceutical composition.
 12. The method of claim9, wherein the compound, or a pharmaceutically acceptable salt thereofis administered in a pharmaceutical composition.
 13. The method of claim7, wherein the pharmaceutically acceptable salt is a fumaric salt of thecompound or a hydrochloride salt of the compound.
 14. The method ofclaim 8, wherein the pharmaceutically acceptable salt is a fumaric saltof the compound or a hydrochloride salt of the compound.
 15. The methodof claim 9, wherein the pharmaceutically acceptable salt is a fumaricsalt of the compound or a hydrochloride salt of the compound.
 16. Themethod of claim 1, wherein the compound is selected from the groupconsisting of:{2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine;{2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine;[(3-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-ethylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(3,5-dimethylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4,5-dimethylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(3-methoxythiophen-2-yl)methyl]({2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-chlorothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-propylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;1-{5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]thiophen-2-yl}ethan-1-ol;[(5-nitrothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;{[5-(methylsulfanyl)thiophen-2-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;(1-benzothiophen-3-ylmethyl)({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;{[5-(2-methylpropyl)thiophen-2-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-butylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;N-methyl-5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]thiophene-2-carboxamide;{2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}({2H,3H-thieno[3,4-b][1,4]dioxin-5-ylmethyl})amine;{[5-(furan-2-yl)thiophen-2-yl]methyl}({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-fluoro-1-benzothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-cyclopentylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;N-ethyl-5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]thiophene-2-carboxamide;2-amino-4-chloro-5-[({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}amino)methyl]thiophene-3-carbonitrile;[(4-phenylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-phenylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-methanesulfonylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4-bromothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-bromothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;{2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}({[5-(thiophen-2-yl)thiophen-2-yl]methyl})amine;[(5-chloro-1-benzothiophen-3-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(5-bromo-4-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4-bromo-5-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(3-bromo-5-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4-bromo-3-methylthiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;[(4,5-dibromothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;and[(3,4-dibromothiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine;or a pharmaceutically acceptable salt thereof.